Identified polynucleotide and polypeptide sequences have numerous applications in, for example, diagnostics, forensics, gene mapping; identification of mutations responsible for genetic disorders or other traits, to assess biodiversity, and to produce many other types of data and products dependent on DNA and amino acid sequences. Proteins are known to have biological activity, for example, by virtue of their secreted nature in the case of leader sequence cloning, by virtue of their cell or tissue source in the case of PCR-based techniques, or by virtue of structural similarity to other genes of known biological activity. It is to these polypeptides and the polynucleotides encoding them that the present invention is directed. In particular, this invention is directed to a novel soluble CD84-like polypeptides and polynucleotides.
Recognition of a specific antigen by a specific T or B cell receptor initiates cellular activation for immune response. A number of co-stimulatory molecules have been described that augment these responses. Some of these co-receptors are also involved in NK cell activation. Co-receptors such as CD2, CD4, CD8, and CD48 belong to the immunoglobulin (Ig) superfamily of surface receptors (Tangye et al (2000) Seminars in Immunology 12, 149-157, incorporated herein as reference). Interactions of these receptors with their cognate ligands on an opposing cell initiates a cascade of signaling events resulting in increased adhesion, cytokine production, cellular activation, and effector functions like cytolytic activities.
CD2, CD48, CD58, CD84, signaling lymphocytic activation molecule (SLAM), 2B4 and Ly-9 are members of the CD2 family that has emerged as a new class of receptors. They are involved in activation of both T and NK cells. Expression of these molecules is mainly restricted to hematopoietic cells, with the exception of CD58 which is found on fibroblasts, CD84 which is detected in Weizmann olfactory tissue and osteoclastomas (Bednarik et al (1998) WO9839448-A2, incorporated herein as reference) and MAX3/CD84 on macrophages dendritic cells and platelets (Krause S W et al (2000) Biochem J 346, 729-736). CD2 family members are 60-100 kDa glycoproteins with characteristic N-terminal non-disulfide bonded Ig variable (IgV) domain. Several of these proteins exhibit unique tyrosine-base motifs in their cytoplasmic domains with the sequence TxYxxV/I/A, where x is any amino acid (SEQ ID NO:13). CD2 cytoplasmic domain has proline rich regions; and glycosyl phosphatidyl inositol-anchored (GPI-anchored) isoforms of CD48 and CD58 are known. Alternative splicing has been described for CD84 and 2B4 generating molecules with identical extracellular domains but exhibiting different cytoplasmic regions. Soluble isoforms of CD48, CD84 and CD58 have also been described (Katsuura et al (1998) Acta Paediatr Jap 40, 580-585). Thus, members of the CD2 family could transduce diverse activating or inhibiting signals into the cell or could serve as soluble ligand.
CD2 family members mediate both homophilic and heterophilic binding. Thus, CD2 binds CD48 and CD58. CD48 binds CD2 on T cells and 2B4 on NK cells. CD48 has also been shown to be the receptor on mast cells for bacterial fimbriae protein fim H (Malaviya R et al (1999) Proc Natl Acad Sci USA. 96, 8110-8115). Engagement of CD48 by 2B4 molecules on NK cells from patients with X-linked lymphoproliferative disease inhibited the cytolysis of virus-infected cells (Parolini et al (2000) J. Exp Med 192, 337-346. Thus, dysregulation of CD2 family member expression may lead to autoimmune disorders or severe immunodeficiencies. Expression of CD48 is upregulated on Epstein-Barr and other virus infected leukocytes. CD48 is also found as a secreted, soluble molecule in these patients and actually correlates with infectious disease activity (Katsuura et al (1998) Acta Paediatr Jap 40, 580-585). In vivo administration of anti CD2 antibody or CD48 induces immunosuppression. Similar results have been reported for anti CD48 antibody administration for bone marrow transplantation studies (Blazar et al (1998) Blood 92, 4453-4463). Soluble CD58 or anti-CD2 antibody also induces sustained T cell unresponsiveness.
Clearly, the immune systems activatory and inhibitory signals are very important for maintaining balance in the immune systems. Systems with a predominance of activatory signals will lead to autoimmunity and inflammation. Immune systems with a predominance of inhibitory signals are less able to challenge infected cells or cancer cells. Isolating new activatory or inhibitory receptors is highly desirable for studying the biological signals transduced by the receptor. Additionally, identifying such molecules provides a means of regulating and treating diseased states associated with autoimmunity, inflammation and infection.